The main objective of the proposed research is to elucidate the molecular mechanism of disorders in the ionic channels of myotonic muscles. The most direct and powerful electrophysiological techniques, the voltage clamp analyses, will be applied to examine the nature of ionic channels in muscles of experimental myotonia. The proposed study will be conducted along five major lines of approach: 1) The overall conductances of the sodium, potassium and chloride channels will be determined by the current-voltage relation; 2) The functional status of each type of channels will be studied by the kinetic analyses using Hodgkin-Huxley parameters; 3) Any abnormality in the internal structure of the channel can be detected by the selectivity of ion permeabilities. This method may also be used to assess any common defects shared by the congenital and dystrophic types of myotonia; 4) The temperature effect of channel conductances will be measured to determine the exact nature of the well known inverse temperature dependence of myotonia. The results of the temperature effect may also be used to differentiate the abnormal ionic channels for further investigation. The quantitative measurement of the heat of activation or reaction may help us to interpret the nature of lipid-protein interaction between the membrane lipids and ionic channels; and 5) Changes in the external molecular structure of the channel can be detected by the change in the pharmacological action of specific drugs. The study of antimyotonic drugs not only will provide insight into the nature of the abnormal ionic channels, but should become useful in the future design of a rational therapeutic approach to myotonia. The data obtained in these five projects will be integrated to help identify the fundamental mechanism underlying the disorders of human myotonia.